HU202506B - Process for producing benzoxazolone derivatives - Google Patents

Abstract

A compound of the formula wherein Q is as defined below, and the pharmaceutically acceptable salts thereof. The compounds are inhibitors of lipoxygenase and cyclooxygenase, and are useful in the treatment of allergic and inflammatory conditions.

Description

This invention relates to benzoxazolone compounds having an aryl or heteroaryl substituted 6-position and to certain 6-aryl or heteroaryl ether derivatives.

These compounds are dual inhibitors of the LO (lipoxygenase) and CO (cyclooxygenase) enzymes and are useful as antiallergic and anti-inflammatory agents in mammals.

129.020. s. U.S. Patent Application Serial No. 5,014,500 (Inventors: Kitura et al.) relates to benoxazolone derivatives containing an alkylamino group at the 6-position and claims that these compounds are LO and CO inbibors .

PCT patent application AWO 85/01289 discloses benzoxazolone and benzothiazoline derivatives containing a halogen, lower alkyl or lower alkoxy substituent on the benzene ring and a side chain bearing a heteroatom. The disclosure claims that these compounds are useful in the treatment of inflammatory conditions and thrombosis.

The present invention relates to a process for the preparation of a novel compound of formula I wherein

Q is -NR1R2 or -XR3,

X is sulfur or oxygen,

R 1 is hydrogen or C 1 -C 4 alkyl,

R2 is pyridyl or a group of formula (Π) in which

Y1 is hydrogen, halogen, C1 -C4 alkoxy, phenoxy, carboxymethyl or di (C1 -C3) alkylamino,

Y 2 is halogen or hydrogen, C 1-3 alkoxy or C 1-4 alkyl,

Y3 is hydrogen, C1-C3 alkoxy or C1-C4 alkyl, and

R3 is a phenyl or pyridyl group for the preparation of a benzoxazolone compound or a pharmaceutically acceptable acid addition salt thereof.

Preference is given to compounds of formula (I) wherein R 1 is hydrogen and R 2 is a group of formula (Π).

Particular preference is given to compounds of formula I wherein Y2 and Y3 are hydrogen at the R2 substituent, and wherein Y3 and Y2 are each C1-C4 alkyl and Y1 is hydrogen. Even more preferred are compounds of formula I wherein, when R2 is Y2 or Y3 is C1-C4 alkyl, it is azomethyl, and when Y1 is halogen, it is chlorine.

The specific compound of the present invention is 6 - [(2-dimethylaminophenyl) amino] -2-benzoxazolinone.

A preferred compound is one in which R1 is hydrogen and R2 is 2-pyridyl.

Another preferred group of compounds of the invention are those compounds of formula I wherein Q is -XR3.

The present invention also relates to the preparation of pharmaceutically acceptable acid addition salts of the compounds of formula (I).

Such salts include the salts of acids which are non-toxic acid addition salts such as hydrochlorides, hydrobromides, sulphates or bisulphates, phosphates, acetates, citrates, fumarates, gluconates, lactates, maleates, succinates, sulphates, tartrates, methanesulates,

The invention further relates to a process for the preparation of a pharmaceutical composition containing the compounds of the formula I as an active ingredient for the treatment of allergic or inflammatory diseases of mammals, in particular humans. These pharmaceutical compositions comprise a pharmaceutically acceptable carrier or diluent and a compound of formula (I), or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) and the pharmaceutical compositions containing them are useful in inhibiting the action of lipoxygenase or cyclooxygenase in mammals, particularly humans.

The novel compounds of formula (I) may be prepared by the reaction scheme.

In this Reaction Scheme, IA denotes compounds of Formula I wherein Q is -NR4R2 wherein R1 and R2 are as defined above, and IB denotes compounds of Formula I wherein Q is -XR3 wherein R3 is as defined above.

In the Reaction Scheme, a hydroxyaniline of formula IIIa wherein R1 and R2 are as defined above is coupled with a benzene diazonium salt to form a compound of formula TV. The benzene diazonium salt required for this purpose, such as benzene diazonium chloride, may be prepared in a conventional manner. The coupling reaction is carried out in a reaction inert solvent such as water. The reactants are generally reacted at a temperature between 0 'C and 5' C and the temperature is allowed to rise to room temperature (usually 25 ° C over a period of 1 hour). The starting hydroxyanilines of formula (IIIa) or known compounds are readily prepared by standard synthesis methods.

The compounds of formula IA wherein R1 is hydrogen are conveniently prepared according to another reaction scheme. This synthesis requires an amine of formula (V) wherein R 2 is as defined above and R 4 is a suitable amine protecting group such as formyl or tert-butoxycarbonyl. The amine (V) is reacted with 2-benzyloxy-4-fluoronitrobenzene (VII) to give (VIII). Similarly, a compound of Formula VI wherein X and R3 are reacted with a compound of Formula VII above to form a compound of Formula IX.

The reaction of the amine (V) with 2-benzyloxy-4-fluoronitrobenzene is carried out in a reaction-inert solvent such as Ν, Ν-dimethylformamide in the presence of a base such as potassium tert-butoxide or potassium carbonate. The reaction temperature depends on the quality of the amino protecting group. For example, when R4 is formyl,

-2GB 202506Β then using potassium carbonate higher, approx. A reaction temperature of 100 'C to 120' C may be used. In the case where R 4 is tert-butoxycarbonyl, the reaction is carried out at room temperature in the presence of potassium tert-butoxide. When R4 is formyl or any base labile group, the product of formula (VHI) is deprotected, which results in the removal of the R4 group in this step. In the case where R4 is tert-butoxycarbonyl, removal is preferably carried out in an acidic medium once the compound of formula IA is obtained, in which case R1 is still tert-BOC.

The same reaction temperature is used for the preparation of the compounds of the formula IX as for the synthesis of the compounds of the formula VHI. This reaction is preferably carried out for about 1 hour. Between 0 'C and 25' C in the presence of potassium tert-butoxide for approx. 0.5 'and 2.0 hours.

Hydrogenation of any of the compounds of formula (IV), (VHI) and (IX) followed by reaction of an intermediate of formula (X) or (XI) with a compound of formula (ΧΠ) in which Z and Z 'are each suitable Removable group allows the preparation of the product of formula IA or IB. Hydrogenation is generally carried out with palladium on carbon in a polar solvent such as ethyl acetate at low pressure (1-3 atm) and at room temperature. Hydrogenation is generally complete within a few hours. The bifunctional intermediate of formulas X and XI can be isolated and purified by conventional means such as recrystallization or chromatography. However, it is preferable not to isolate this material but to contact the reagent of formula XII in situ. This one-step process is conveniently carried out after the hydrogenation reaction by adding about equimolar amount of the compound of formula XII with or without solvent. Representative compounds of formula (XQ) include phosgene, dimethyl carbonate, diethyl carbonate, urea, Ν, Ν-carbodimidazole, methyl chloroformate and trichloromethyl chloroformate. Trichloromethyl chloroformate is preferably used.

The solvent used for this coupling is either the same as that used for hydrogenation or is a solvent which is miscible with the hydrogenation solvent and is inert. The preferred reaction medium is ethyl acetate. The reaction is carried out at a temperature between 0 'C and 25' C, preferably about 5 ° C. At this temperature, the reaction is generally substantially complete within 5 to 60 minutes. The desired benzoxazolones of formulas IA and IB are then purified by conventional means such as recrystallization or chromatography.

Compounds of formula IA wherein R1 is methyl are preferably prepared by methylation of the 5-position amino group of corresponding compounds of formula IA wherein R1 is hydrogen. This is preferably accomplished by first forming an immuno-4mum derivative of the compound of formula IA with formaldehyde and then reducing the ammonium intermediate. The reagent suitable for this purpose is sodium borohydride, which is used in an excess (e.g., 5 moles per mole of Formula LA, formaldehyde and sodium borohydride are reacted at about 0 ° C to 25 ° C in an inert solvent such as tetrahydrofuran. The product can be isolated and purified by conventional means.

Pharmaceutically acceptable salts of the novel compounds of the present invention are readily prepared by reacting said compound with a stoichiometric amount of an appropriate grade mineral or organic acid in aqueous solution or in a suitable organic solvent. The salts can then be recovered by precipitation or by evaporation of the solvent.

The compounds of the invention are inhibitors of the cyclooxygenase and lipoxygenase enzymes. Their activity was demonstrated in an assay using cells in the peritoneal cavity of rats that determine the effect of these compounds on arachidonic acid metabolism.

In this assay, some preferred compounds exhibit low IC 50 values in the range of 1-10 moles, indicating inhibition of lipoxygenase and cyclooxygenase.

The ability of the compounds of the invention to inhibit both enzymes makes them useful in the control of symptoms induced by arachidonic acid metabolites in mammals. The compounds of the invention are therefore valuable for the prevention and treatment of disease states caused by the accumulation of a metabolite of arachidonic acid. Thus, your examples are useful in the treatment of allergic bronchial asthma, skin disorders, rheumatoid arthritis, osteoarthritis and thrombosis.

The anti-inflammatory activity of the compounds of the present invention can be determined by the standard carrageenin-induced rat foot-test (CA.Winter et al., Proc. Soc. Exp. Biol. 111, 544, 1962), in which the preferred compounds are more than 50%. inhibition at 50 mg / kg orally.

Thus, the pharmaceutically acceptable salts of the compounds of formula I are particularly useful in the treatment or amelioration of allergic or inflammatory diseases in humans.

For the treatment of the above various diseases, the compounds of the formula I and their pharmaceutically acceptable salts may be administered to humans alone or preferably in combination with a pharmaceutically acceptable carrier or diluent, according to standard pharmaceutical practice. The compounds may be administered by a variety of conventional routes of administration, including oral, parenteral, and inhalation. In the case of oral administration, the subject's body weight is approx. The dosage range is 0.1 to 20 mg / kg / day, preferably 0.1 to 1.0 mg / kg / day or more per day. In the case of parenteral administration, an effective dose is about 10 mg / kg of the subject to be treated.

-3HU 202506Β

6

0.1-1.0 mg / kg / day. In some cases, lower or higher doses may be required, as the dosage will necessarily vary with the age, weight and response of the individual, the severity of the patient's symptoms, and the potency of the particular compound being administered.

For oral administration, the compounds of formula (I) may be administered, for example, in the form of tablets, powders, syrups or capsules, or as aqueous solutions or suspensions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch, and lubricating agents such as magnesium stearate are added.

A useful diluent for capsules is lactose and dried corn starch. When an aqueous suspension is required for oral use, the active component is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are generally prepared and the pH of the solutions adjusted and buffered. For intravenous use, the total concentration of the solute should be checked to render the product isotonic.

The invention is illustrated by the following examples. However, it is to be understood that the invention is not limited to the details of these examples. Nuclear Magnetic Resonance (NMR) spectra, unless otherwise noted, were recorded at 270 MHz in a solution of perdeuterodimethylsulfoxide (DMSO-d6) and peak positions are reported in parts per million (ppm) below tetramethylsilane. The shape of the peaks is denoted as singlet; mmultiplet; b- wide.

Example 1

6- (phenylamino) -2-benzoxazolone

2-Phenyldiazzo-5- (phenylamino) phenol (1.0 g, 3.46 mmol) was hydrogenated with 200 mg of 5% palladium on carbon in ethyl acetate for 1.5 hours. To this hydrogenated solution is added 3.46 mmol of trichloromethyl10 chloroformate at 5 'C. Stirring was continued at room temperature for 10 minutes. Water (5 mL) was added to the reaction mixture and stirred at room temperature for 30 minutes. Palladium on carbon was filtered off and a saturated aqueous sodium bicarbonate solution was added to the filtrate. The organic material was extracted with ethyl acetate (3 x 30 mL). The combined ethyl acetate extracts were combined, washed with alkali, dried over magnesium sulfate and concentrated under reduced pressure. Obtained as an oily crude product. The oil was chromatographed on 20 silica gel eluting with ethyl acetate / hexane (1: 1). 496 mg of the title compound are obtained, m.p. 167-168 ° C.

IR (Nujol): 3500,3450,3280,1740,1650 cm ^1st n-NMR: 11.38 (bs, 1H); 8.07 (1H, s), 7.20 (2H, t), 6.75-7.01 (6H, m).

H, 4.46; N, 12.38. Found: C, 68.94; H, 4.45; N, 12.35.

2-6. examples

Following the procedure of Example 1, starting from the appropriate reagents, the following compounds of formula (Ia) were prepared:

I

Example number R2 Op.'C IR (cm ^_1) NMR Second (2) 144-145 3400.1740 11.36 (1H, bs), 7.99 (1H, s), 7.11-6.78 (5H, m), 6.60 (1H, d), 2.23 (3H, s). Third (3) 226-227 3300.1760 11.44 (1H, broad s), 8.27 (2H, s), 7.98 (1H, d), 7.39-7.34 (1H, m), 7.22-7.17 (1H, m), 7.06 (1H, d), 6.91-6.88 (1H, m). 4th (4) 146-147 3430.3250, 1760.1730 11.33 (1H, broad s), 7.28 (1H, s), 7.16 (1H, d), 7.08-7.06 (2H, m), 6.93 (1H, d, J = 8.06Hz), 6.88-6.81 (2H, m), 6.72 (1H, dd, J) -8.06Hz), 2.19 (3H, s). 5th (5) 160-161 3350.1755 11.32 (1H, broad s), 7.92 (1H, s), 7.03 (2H, d), 6.95-6.90 (un m), 6.80 (1H, m), 2.21 (3H, s). 6th (6) 140 3410.3225, 1775.1735 11.33 (1H, bs), 7.94 (1H, bs), 7.05-7.01 (2H, m), 6.95-6.91 (4H, m), 6.80 ( 1H, dd), 2.48 (2H, t), 1.57-1.45 (2H, m), 1.37-1.23 (2H, m), 0.89 (3H, t).

Example 7 60

6 - [(4-chlorophenyl) amino] -2-benzoxazolone

5 - [(4-Chlorophenyl) amino] -1-benzyloxy-2-nitrobenzene (2.07 g, 5.83 mmol) was hydrogenated with 1.00 g of 5% palladium on carbon in ethyl acetate for 2 hours. To this hydrogenated solution is added 5.83 mmol trichloromethyl chloroformate at 5 ° C. Stir at room temperature for 30 minutes. To the reaction mixture was added water (20 mL) and stirred at room temperature for 15 minutes. Palladium on carbon was filtered off and saturated sodium bicarbonate solution was added to the filtrate. The organic material was extracted twice with 50 ml of ethyl acetate-4HU 202506Β. The combined ethyl acetate extracts were washed with alkali, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was obtained as a solid.

The crude product was recrystallized from ethyl acetate-n-hexane. 560 mg of the title compound are obtained, m.p. 189-191 ° C.

IR (Nujol): 3440.1760 cm ^1st

O-NMR Spectrum 11.41 (1H, bs), 8.22 (1H, s), 7.23-7.19 (2H, m), 7.02-6.95 (4H, m) , 6.86 (1H, dd).

Analysis: Calculated for C 13 H 10 N 2 O 2 Cl: C, 59.89; H, 3.48; N, 10.75. Found: C, 59.96; H, 3.47; N, 10.80.

8-17. examples

Following the procedure described in Example 7, starting from the appropriate reagents, the following compounds were prepared:

II. spreadsheet

Example number R2 Op IRfcm ' ¹ ) NMR 8th (8) 156-157 3360.3250 1740 11.37 (1H, br), 8.01 (1H, s), 7.14-6.80 (6H, m), 6.63 (1H, d), 2.50 (2H, q, J = 7.3Hz), 1.16 (3H, t, J = 7.3Hz). 9th (9) 193-194 3420, 1755, 1740 11.31 (1H, br), 7.85 (1H, s), 6.98-6.81 (3H, m), 6.77-6.74 (3H, m), 2.15 (3H, s), 2.13 (3H, s). 10th (10) 190-191 3400,3200, 1770,1747 11.31 (1H, bs), 7.14 (1H, s), 7.12-7.02 (3H, m), 6.80 (1H, d), 6.29 (1H, d, J = 2.20Hz), 6.16 (1H, dd, J = 8.06Hz and 2.20Hz), 2.12 (6H, s). 11th (11) 157-159 3,380,3300, 1770,1740 11.28 (1H, broad s), 7.77 (1H, broad s), 7.01-6.92 (2H, m), 6.91 (1H, d, J = 8.06Hz), 6.88-6.83 (3H, m), 6.71 (1H, dd, J = 8.06Hz), 3.70 (3H, s) ). 12th (12) 127-128 3400.1760, 1625.1605 11.33 (1H, bs), 7.28 (1H, bs), 7.10-6.79 (7H, m), 3.81 (3H, s). 13th (13) 198-199 3350.3225 1782 11.35 (1H, broad), 7.97 (1H, s), 7.00 (1H, d), 6.95 (1H, d), 6.85 (1H, dd), 5.29 (2H, s), 3.71 (6H, s), 3.59 (3H, s). 14th (14) 170 (Dec) 3420, 1755, 1718 12.19 (1H, bs), 11.35 (1H, bs), 8.04 (1H, s), 7.08 (2H, d), 6.98-6.85 (4H, m) , 6.82 (1H, d), 3.44 (2H, s). 15th (15) 152 1760.1740 11.22 (1H, broad s), 7.77 (1H, s), 7.43 (1H, d, J = 8.06Hz), 7.24 (1H, d, J = 8.06Hz), δ , 84 (1H, d, J = 8.80Hz), 6.46 (1H, d, J = 2.2Hz), 6.28 (1H, dd, J = 8.80 and 2.20Hz), 2.36 (3H, s). 16th (16) 158 3420.1760 11.36 (1H, bs), 8.05 (1H, bs), 7.38-6.92 (9H, m), 6.83 (1H, dd). 17th (17) 209 (Dec) 3300.1770, 1735 12.21 (1H, bs), 7.59 (1H, bs), 6.94 (2H, d, J-8.79Hz), 6.86 (1H, d, J-8.79Hz), 6.75-6.62 (4H, m), 2.82 (6H, s).

18-20. EXAMPLES Starting from shoot reagents, the following general formula (Ib) is used

The procedure described in Example 7 was followed and the following compounds were prepared:

III. spreadsheet

Example R3X-Op.'C1R (cm ^-1 ) NMR number

18. (18) 172-174 3250.1770.1625, 11.64 (1H, broad), 7.41-7.33 (2H, m), 7.13-7.08

1600,1225,1090, (3H, m), 6.99-6.94 (2H, m), 6.82 (1H, m),

960

-5HU 202506Β

III. Continue Table

Example number R3X- Op.'C IRÍcm ' ¹ ) NMR 19th (19) 182-183 2,700,1790,1265, 1225 11.69 (1H, bs), 8.36-8.32 (2H, m), 7.42-7.34 (2H, m), 7.22 (1H, d, J-2.2Hz) , 7.12 (1H, d, J-8.79Hz), 6.90 (1H, dd, J-8.79Hz and 2.2Hz). 20th (20) 165-167 3,200,1900,1775,950 11.83 (1H, broad s), 7.40-7.12 (8H, m).

Example 21

6 - [(2,6-Diethylphenyl) amino] -2-benzoxazolone 15

N-tert-butoxycarbonyl-4 - [(2,6-diethylphenyl) amino] -2-benzyloxynitrobenzene (1.9 g, 4.9 mol) was hydrogenated over 0.5 g of 5% palladium on carbon. ml of ethyl acetate for 2 hours. Palladium on carbon was removed by filtration, the filtrate was cooled to 5 ° C, and

Triethylamine (4.10 mmol) was added. Trichloromethyl chloroformate (4.09 mmol) was added to the reaction mixture at 5 ° C. Stirring was continued at room temperature for 30 minutes. To the reaction mixture was added water (20 mL) and stirred at room temperature for 15 minutes. A saturated aqueous sodium bicarbonate solution was added and the product was extracted with ethyl acetate (2 x 120 mL).

The combined ethyl acetate extracts were washed with alkali and dried over magnesium sulfate. After removal of the solvent, the crude oil was purified by chromatography on silica gel eluting with ethyl acetate / n-hexane. 1.21 g of N- (tert-butoxycarbonyl) -6 - [(2,6-diethylphenyl) amino] -2-benzoxazolone are obtained; Yield: 80%. Nuclear Magnetic Resonance Spectrum 11.58 (1H, bs), 7.32-7.19 (4H, m), 35

6.96 (1H, d, J-8.8Hz), 6.70 (1H, dd, J-8.8Hz), 2.44 (4H, m), 1.36 (9H, 2) and 1, 09 (6H, t) ppm.

To a stirred solution of 4.1 g (11.1 mmol) of N-tert-butoxycarbonyl-6 - [(2,6-diethylphenyl) amino] -2-benzoxazolone in 50 mL of 40 dichloromethane at room temperature Trifluoroacetic acid (111 mmol) was added. Stirring was continued for 2 hours. After removal of the solvent, water was added to the reaction mixture. The organic material was extracted with ethyl acetate (2 x 50 mL). The combined extracts were washed with brine and dried over magnesium sulfate. The dried solution was evaporated and the residue was recrystallized from ethanol. 2.51 g of N- (trifluoroacetyl) -6 - [(2,6-diethylphenyl) amino] -2-benzoxazolone are obtained in 50% yield (59%).

To a solution of this product (1.36 g, 3.6 mmol) in tetrahydrofuran (14 mL) was added a solution of lithium hydroxide monohydrate (749 mg, 17.9 mmol) in water (3.5 mL). Stirring was continued at 60 ° C for 2 hours 55 The solvent was removed and water was added to the resulting oil. The organic material was extracted with ethyl acetate (2 x 20 mL). The combined extracts were washed with brine and dried over magnesium sulfate. The dried solution was concentrated and chromatographed on silica gel with ethyl acetate / hexane 1: 1 as eluent. 0.92 g (90%) of the title compound are obtained. Melting point: 140-141 ° C.

IR (KBr): 3400,3200,3000,1760,1645 cm ^-1 . 65'H NMR: 11.1 (1H, bs), 7.2 (1H, bs), 7.15 (3H, s), 6.78 (1H, d, J-8, 1Hz) , 6.26 (1H, d, J-2.2Hz), 6.13 (1H, dd, J-8.1 and 2.2Hz), 2.47 (4H, g, J-7.3Hz), 1.04 (6H, t, J = 7.3Hz).

Analysis calculated for C17 H18 N2 O2: C, 72.33; H, 6.43; N, 9.92. Found: C, 72.19; H, 6.29; N, 9.90.

Example 22

6 - [(2-Dimethylaminophenyl) amino] -2-benzoxazole

The procedure of Example 21 was followed; starting from the corresponding N-tert-butoxycarbonylaniline derivatives to give the title compound.

Example 23

To a stirred solution of 6- (N-methyl-N-phenylamino) -2-benzoxazolone in mole sulfuric acid and 40% aqueous formaldehyde was added dropwise a suspension of sodium borohydride and 6- (phenylamino) -2-benzoxazolone. ° C. Dichloroethane was added to the reaction mixture, and the aqueous layer was made basic by the addition of 5% sodium bicarbonate solution. The organic layer was separated and washed with brine. The dried solution was concentrated under reduced pressure and the residue was recrystallized from dichloromethane / ether. The title compound is obtained. Melting point: 136-137 ° C.

IR (KBr): 3290, 1790, 1740, 1600 cm ^-1 .

1 H NMR Spectrum: 11.52 (1H, bs), 7.247.18 (2H, m), 7.08-7.02 (2H, m), 6.88-6.79 (4H, m) ), 3.22 (3H, s).

The preparation

Aniline (29.6 mmol) was dissolved in aqueous hydrochloric acid (5.7 mL) (concentrated hydrochloric acid / 6 mL water) and cooled to 0 ° C. To this solution is added a solution of 2.06 g of sodium nitrite in 29 ml of water at 05 ° C. Stirring was continued for 30 minutes

Dissolve 5.03 g (27.5 mmol) of m-hydroxydiphenylamine in aqueous sodium hydroxide solution (3.4 g of sodium hydroxide in 34 ml of water). Add the above solution at 0-5 ° C. Within 30 minutes. Stirring was continued at room temperature for 1 hour. The organic material was extracted with ethyl acetate (2 x 20 mL). The combined extracts were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude oil is obtained. The oil was chromatographed on silica gel eluting with chloroform. 2.93 g of the expected compound are obtained. Melting point: 176-177 ° C.

1 H NMR Spectrum 13.26 (1H, bs), 9.11

-6H 202506Β (1H, broad s), 7.80-7.05 (1H, m), 6.68 (1H, dd, J-8.8 and 2.2Hz), 6.48 (1H, broad s) ).

In a similar manner, starting from the corresponding diphenylanilines and using the procedure described in Preparation A, the following 2-phenyl-thiazo-5- (phenylamino) phenols are prepared:

2 Phenyldiazo-5 - [(3-tolyl) amino] phenol,

2 fenüdiazo-5 - [(2-tolyl) amino] phenol,

2 Phenyldiazo-5 - [(4-tolyl) amino] phenol,

2 Phenyldiazo-5- [4- (n-butyl) -phenyl-amino] -phenol,

2 fenüdiazo-5 - [(2-pyridyl) amino] phenol.

3 preparations

4 - [(4-Chloro-phenyl) -amino] -2-benzyloxy-nitrobenzene

3.47 g (22.3 mmol) of N-formyl-p-chloraniline, 6.06 g (24.5 mmol) of 4-fluoro-2-benzyloxynitrobenzene and 6.16 g (44.6 mmol) of potassium The carbonate mixture was heated in dimethylformamide (30 ml) under nitrogen for 2 hours at 120 ° C. The reaction mixture was cooled, water (50 mL) was added and the resulting precipitate was collected by recrystallization from Aceton to give 3.41 g (43%) of the title compound.

Melting point: 176-177'C.

1 H NMR Spectrum: 9.24 (1H, s), 7.94 (1H, d, J = 8.8Hz), 7.50-7.33 (7H, m), 7.17-7. 13 (2H, m), 6.76 (1H, d, J = 2.2Hz), 6.62 (1H, dd, J-8.8 and 2.2Hz), 5.27 (2H, s).

Similarly, starting from the corresponding N-formylaniline derivatives and using the procedure described in Preparation B, the following benzyloxynitrobenzenes are prepared:

4 - [(3-ethylphenyl) amino] -2-benzyloxy-nitrobenzene,

4 - [(3,4-dimethylphenyl) amino] -2-benzyloxynitrobenzene,

4 - [(2,6-dimethylphenyl) amino] -2-benzyloxynitrobenzene,

4 - [(4-methoxyphenyl) amino] -2-benzyloxy-nitrobenzene,

4 - [(2-methoxyphenyl) amino] -2-benzyloxy-nitrobenzene,

4 - [(3,4,5-trimethoxyphenyl) amino] -2-benziloxinitrobenzol,

4 - [(4-carboxymethyl-phenyl) amino] -2-benziloxinitrobenzol,

4 - [(2,6-dichloro-3-methyl-phenyl) -amino] -2-benzyl-xynitrobenzene,

4 - [(4-phenoxyphenyl) amino] -2-nitrobenzene benziloxx,

4 - [(4-dimethylaminophenyl) amino] -2-benzüoxinitrobenzol.

Preparation C

N- (tert-butoxycarbonyl) -4 - [(2,6-diethyl-phenyl) amino] -2-benzyloxy-nitrobenzene

1.89 g (7.59 mmol) of N- (tert-butoxycarbonyl) 2,6-diethylaniline, 1.70 g (7.59 mmol) of 4-fluoro-2-benzyloxynitrobenzene and 0.85 A mixture of potassium tert-butoxide (g, 7.59 mmol) in dimethylformamide (112 mL) was stirred under nitrogen at room temperature for 9 hours. The dimethylformamide was removed in vacuo and water was added. The organic material was extracted with ethyl acetate (2 x 30 mL). The combined extracts were washed with brine, dried over magnesium sulfate and evaporated. The crude product was recrystallized from acetone to give 3.40 g (95%) of the title compound. .

IR (KBr): 3000.1720 cm ^1st

O-NMR Spectrum: 7.88 (1H, d, J-9.5Hz), 7.41-7.19 (9H, m), 6.73 (1H, dd, J-9.5 and 2, 2Hz), 5.15 (2H, s), 2.3 (4H, m), 1.35 (9H, s), 1.03 (6H, t) ppm.

Similarly, starting from the corresponding N-tert-butoxycarbonylaniline derivatives and following the procedure described in Preparation C, N- (tert-butoxycarbonyl) -4 - [(2-dimethylaminophenyl) amino] - 2 is obtained with oxy-nitrobenzene.

Claims (11)

A process for the preparation of a new Formula (I) wherein: Q is -NR1R2 or -XR3, X is sulfur or oxygen, R3 is phenyl or pyridyl, R 1 is hydrogen or C 1-4 alkyl, R2 is a group of formula (Π) or (ΙΠ) - in which Y 1 is hydrogen, halogen, C 1 -C 4 alkoxy, phenoxy, carboxymethyl or di (C 1 -C 3) alkylamino, Y 2 is hydrogen, C 1-4 alkyl, C 1-3 alkoxy, or halogen, and Y3 is a hydrogen atom, a C1-C3 alkoxy group or a C1-C4 alkyl group benzoxazolone, or a pharmaceutically acceptable acid addition salt thereof, characterized in that a compound of formula (X) or an optionally protected derivative thereof, Z and Z are the same or different, each with a suitable removable group compound, the optional protecting group is removed and, if desired, a R 1 group is introduced by alkylation into the compound of formula (I) and / or or a pharmaceutically acceptable salt thereof. A process for the preparation of a compound of formula I according to claim 1, wherein Q is -NR 1 R 2, R 1 is hydrogen, and R 2 is a group of formula II, wherein the starting materials are suitable. 3. A process according to claim 2 for the preparation of a compound of formula I wherein Y1, Y2 and Y3 are each hydrogen, characterized in that starting materials are suitable. 4. A process for the preparation of compounds of formula I according to claim 2, wherein Y3 and Y2 are independently C1-C4 alkyl and Y1 is hydrogen, characterized in that -7GB 202506Β ¹³ out of the box. The process for the preparation of a compound of formula I according to claim 1, wherein Q is -NR 1 R 2, wherein R 1 is hydrogen and R 2 is pyridyl, characterized in that starting materials are suitable. 6. A process according to claim 1 for the preparation of compounds of formula I wherein Q is -NR 1 R 2, wherein R 1 is methyl and R 2 is a group of formula (Π), wherein starting materials are suitable. A process for the preparation of a compound of formula (I) according to claim 1, wherein Q 15 is -XR 3 and X is sulfur, characterized in that starting materials are suitable. 8. A process according to claim 1 for the preparation of compounds of general formula (I) wherein Q is -XR3 and X is oxygen, characterized in that starting materials are suitable. 9. A process according to claim 1, wherein the compound of formula X is prepared by hydrogenation of a compound of formula IV, VIII or IX wherein R4 is a suitable amino protecting group. . 10. A process according to claim 9 wherein the amino protecting group is formyl or tert-butoxycarbonyl. 11. A process according to any one of claims 1 to 3, wherein the compound of formula ZCOZ 'is phosgene, dimethyl carbonate, diethyl carbonate, urea, N, N-carbodiimidazole, methyl chloroformate or trichloromethyl chloroformate.